The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of proteins and other biomolecules associated with target diseases. One important class of proteins that has been the subject of extensive study is the family of 5-hydroxytryptamine (serotonin, 5-HT) receptors. The 5-HT7 receptor discovered in 1993 belongs to this family and has attracted great interest as a valuable new drug target (Terrón, J. A. Idrugs, 1998, vol. 1, no. 3, pages 302-310: “The 5HT7 receptor: A target for novel therapeutic Avenues?”).
5-HT7 receptors have been cloned from rat, mouse, guinea pig and human cDNA and exhibit a high degree of interspecies homology (approx. 95%), but it is unique in that it has a low sequence homology with other 5-HT7 receptors (less than 40%). Its expression pattern, in particular structures of the central nervous system (CNS) (highest in hypothalamus (in particular suprachiasmatic nuclei) and thalamus) and other peripheral tissues (spleen, kidney, intestinal, heart and coronary artery), implicates the 5-HT7 receptor in a variety of functions and pathologies. This idea is reinforced by the fact that several therapeutic agents, such as tricyclic antidepressants, typical and atypical antipsychotics and some 5-HT2 receptor antagonists, display moderate to high affinity for both recombinant and functional 5-HT7 receptors.
Functionally, the 5-HT7 receptor has been implicated in regulation of circadian rhythms in mammals (Lovenberg, T. W. et al. Neuron, 1993, 11:449-458 “A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of circadian rhythms”). It is known that disruption of circadian rhythms is related to a number of CNS disorders including depression, seasonal affective disorder, sleep disorders, shift worker syndrome and jet lag among others.
Distribution and early pharmacological data also suggest that the 5-HT7 receptor is involved in the vasodilatation of blood vessels. This has been demonstrated in vivo (Terrón, J. A., Br J Pharmacol, 1997, 121:563-571 “Role of 5-HT7 receptors in the long lasting hypotensive response induced by 5-hydroxytryptamine in the rat”). Thus selective 5-HT7 receptor agonists have a potential as novel hypertensive agents.
The 5-HT7 receptor has also been related with the pathophysiology of migraine through smooth muscle relaxation of cerebral vessels (Schoeffter, P. et al., 1996, Br J Pharmacol, 117:993-994; Terrón, J. A., 2002, Eur. J. Pharmacol., 439:1-11 “Is the 5-HT7 receptor involved in the pathogenesis and prophylactic treatment of migraine?”). In a similar manner, involvement of 5-HT7 in intestinal and colon tissue smooth muscle relaxation makes this receptor a target for the treatment of irritable bowel syndrome (De Ponti, F. et al., 2001, Drugs, 61:317-332 “Irritable bowel syndrome. New agents targeting serotonin receptor subtypes”). Recently, it has also been related to urinary incontinence (British J. of Pharmacology, Sep. 2003, 140(1) 53-60: “Evidence for the involvement of central 5HT-7 receptors in the micurition reflex in anaesthetized female rats”).
In view of the potential therapeutic applications of agonists or antagonists of the 5HT7 receptor, a great effort has been directed to find selective ligands. Despite intense research efforts in this area, very few compounds with selective 5-HT7 antagonist activity have been reported (Wesolowska, A., Polish J. Pharmacol., 2002, 54: 327-341, “In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors”).
WO 97/48681 discloses sulfonamide derivatives, which are 5-HT7 receptor antagonists, for the treatment of CNS disorders. The sulphur atom is linked to an aromatic group and to a N-containing heterocyclic group, optionally containing a further heteroatom selected from oxygen or sulphur.
WO 97/29097 describes sulfonamide derivatives for the treatment of disorders in which antagonism of the 5-HT7 receptor is beneficial. The sulphur atom is linked to an aromatic group and to a C1-C6 alkyl substituted N atom.
WO97/49695 describes further sulfonamide derivatives in which the N linked to the sulphur atom is also fully substituted, for example forming part of a piperidine.
WO 03/048118 describes another group of 5HT7 receptor antagonists. In this case aryl and heteroaryl sulfonamide derivatives wherein the sulfonamide group is a substituent on a cycloalkane or cycloalkene ring which additionally bears an amino substituent. The N linked to sulphur atom is fully substituted.
WO99/24022 discloses tetrahydroisoquinoline derivatives for use against CNS disorders and binding to serotonin receptors, in particular 5-HT7.
WO 00/00472 refers to compounds which are 5-HT7 receptor antagonists. The compounds contain a N-containing fused heterocycle such as tetrahydroisoquinoline.
EP 21580 and EP 76072 describe sulfonamide compounds having antiarrhythmic activity, corresponding to the formula R2N(CH2)n—NH—SO2R1, 5-HT7 activity is not mentioned.
EP 937715 A1 refers to a tetrahydrobenzoindole compound that binds selectively to a serotonin receptor subtype 5-HT7 vs 5-HT2.
There is still a need to find compounds that have pharmacological activity towards the receptor 5-HT7, being both effective and selective, and having good “drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion.